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Áreas de investigación Ciencias Biomédicas y Clínicas Oncología y carcinogénesis Objetivos moleculares
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Ciencias Biomédicas y Clínicas
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Objetivos moleculares
Definición de los estados de células T asociados con la respuesta a la inmunoterapia de punto de control en el melanoma

Definición de los estados de células T asociados con la respuesta a la inmunoterapia de punto de control en el melanoma

Moshe Sade-Feldman ¹, Keren Yizhak ², Stacey L Bjorgaard ³, John P Ray ², Carl G de Boer ², Russell W Jenkins ⁴, David J Lieb ², Jonathan H Chen ⁵, Dennie T Frederick ⁶, Michal Barzily-Rokni ⁶, Samuel S Freeman ⁷, Alexandre Reuben ⁸, Paul J Hoover ⁹, Alexandra-Chloé Villani ¹, Elena Ivanova ¹⁰, Andrew Portell ¹⁰, Patrick H Lizotte ¹⁰, Amir R Aref ¹⁰, Jean-Pierre Eliane ¹¹, Marc R Hammond ⁶, Hans Vitzthum ⁶, Shauna M Blackmon ⁶, Bo Li ¹², Vancheswaran Gopalakrishnan ⁸, Sangeetha M Reddy ⁸, Zachary A Cooper ¹³, Cloud P Paweletz ¹⁰, David A Barbie ¹⁴, Anat Stemmer-Rachamimov ¹¹, Keith T Flaherty ¹⁵, Jennifer A Wargo ¹³, Genevieve M Boland ¹⁶, Ryan J Sullivan ¹⁵, Gad Getz ¹⁷, Nir Hacohen ¹

Moshe Sade-Feldman ¹, Keren Yizhak ², Stacey L Bjorgaard ³

¹Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
²Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
³Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁴Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
⁵Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA.
⁶Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
⁷Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Biomedical Informatics, HMS, Boston, MA, USA.
⁸Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Brigham & Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA, USA.
¹⁰Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA.
¹¹Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA.
¹²Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Virology, Harvard Medical School, Boston, MA, USA.
¹³Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
¹⁵Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
¹⁶Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, HMS, Boston, MA, USA.
¹⁷Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA.

⁰Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.

Cell +

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3 de noviembre de 2018

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3 de noviembre de 2018

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Ver abstracta en PubMed

Resumen

Este resumen es generado por máquina.

Los investigadores identificaron dos estados de células T CD8+ en pacientes con melanoma sometidos a una terapia de bloqueo de punto de control inmunológico. El factor de transcripción TCF7 predice resultados positivos, ofreciendo nuevos objetivos para mejorar la inmunoterapia contra el cáncer.

Área De La Ciencia

Inmunología
En el campo de la oncología
La genómica

Sus Antecedentes

Las terapias de bloqueo de puntos de control inmunológico han transformado el tratamiento del cáncer, particularmente para el melanoma avanzado.
Sin embargo, muchos pacientes no responden o eventualmente sucumben a la enfermedad, lo que requiere la identificación de predictores de respuesta y objetivos terapéuticos.
Comprender el microambiente inmune del tumor es crucial para mejorar la eficacia de la inmunoterapia.

Objetivo Del Estudio

Identificar los factores asociados con el éxito o el fracaso de la terapia de control inmunológico en el melanoma.
Definir estados celulares inmunes distintos dentro del microambiente tumoral que se correlacionan con los resultados clínicos.
Descubrir nuevos objetivos para mejorar la inmunidad antitumoral.

Principales Métodos

Se realizó la secuenciación de ARN unicelular (scRNA-seq) en 16.291 células inmunes de 48 muestras de tumores de pacientes con melanoma.
Se utilizó el análisis de agrupación para definir estados distintos de células T CD8+.
Se utilizó inmunohistoquímica para visualizar la expresión de TCF7 en muestras tumorales y se realizó un perfil epigenético.

Principales Resultados

Se identificaron dos estados distintos de células T CD8+, correlacionados con la regresión o progresión del tumor.
La expresión de TCF7 (factor de células T 7) en las células T CD8+ surgió como un predictor del resultado clínico positivo en una cohorte de pacientes independientes.
El paisaje epigenético y la clonalidad de estos estados de células T fueron delineados, revelando vulnerabilidades potenciales en las células T agotadas.

Conclusiones

Este estudio revela distintos estados de células T CD8+ asociados con la respuesta a los inhibidores del punto de control en el melanoma.
TCF7 es un potencial biomarcador predictivo para la respuesta a la inmunoterapia.
Dirigirse a nuevas combinaciones de factores en las células T agotadas puede aumentar la inmunidad antitumoral y mejorar los resultados de los pacientes.

Palabras clave:

Las células T CD8 ((+) TCF7 (en inglés) Inmunoterapia contra el cáncer Bloqueo de los puntos de control ADN de una sola célula

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